Variant rs369065966 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000057.4(BLM):c.2357G>A(p.Arg786Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,636 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

BLM
NM_000057.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 9.73

Variant links:

Genes affected

BLM (HGNC:1058): (BLM RecQ like helicase) The Bloom syndrome is an autosomal recessive disorder characterized by growth deficiency, microcephaly and immunodeficiency among others. It is caused by homozygous or compound heterozygous mutation in the gene encoding DNA helicase RecQ protein on chromosome 15q26. This Bloom-associated helicase unwinds a variety of DNA substrates including Holliday junction, and is involved in several pathways contributing to the maintenance of genome stability. Identification of pathogenic Bloom variants is required for heterozygote testing in at-risk families. [provided by RefSeq, May 2020]

BLM links:

BLM (HGNC:):

BLM links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BLM	NM_000057.4 linkuse as main transcript	c.2357G>A	p.Arg786Lys	missense_variant	11/22	ENST00000355112.8	NP_000048.1	P54132

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BLM	ENST00000355112.8 linkuse as main transcript	c.2357G>A	p.Arg786Lys	missense_variant	11/22	1	NM_000057.4	ENSP00000347232.3		P54132

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251474

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461636

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000602

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bloom syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jul 29, 2021	The BLM c.2357G>A (p.Arg786Lys) missense change has a maximum subpopulation frequency of 0.0018% in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/variant/15-91312412-G-A). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. This variant has been identified in 1 of 1358 control individuals collected as part of non-cancer studies (PMID: 29641532). To our knowledge, this variant has not been reported in individuals with Bloom syndrome. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_supporting. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 15, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 786 of the BLM protein (p.Arg786Lys). This variant is present in population databases (rs369065966, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with BLM-related conditions. ClinVar contains an entry for this variant (Variation ID: 567621). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BLM protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2022

The p.R786K variant (also known as c.2357G>A), located in coding exon 10 of the BLM gene, results from a G to A substitution at nucleotide position 2357. The arginine at codon 786 is replaced by lysine, an amino acid with highly similar properties. This alteration was identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This alteration was also identified in a cohort of early onset colorectal cancer patients (Belhadj S et al. Hum Mutat, 2020 09;41:1563-1576). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

T;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.74

D;D

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

0.77

N;.

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.8

D;D

REVEL

Uncertain

0.56

Sift

Uncertain

0.0080

D;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.13

B;.

Vest4

0.73

MVP

0.86

MPC

0.48

ClinPred

0.83

GERP RS

5.4

Varity_R

0.80

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over